Noise-induced hearing loss is a serious public health problem. Prevention and treatment of noise-induced ear damage is possible with certain drugs but our understanding of the mechanisms involved in their actions is still rudimentary. A wide variety of drugs have been found to provide protection from hearing loss in experimental animals but there is no unifying framework upon which to formulate a theoretical explanation for the efficacy of the disparate drugs that have been found to be effective. This project identifies a prospective master gene, the activity of which controls and coordinates the activity of a large number of other genes that are involved in cellular stress responses. The gene is called Nrf2. Work on effects of Nrf2 activation in other tissues have identified it as a therapeutic target for treatment of a wide variety of disorders and there are good reasons to believe that it should also be important for treatment of disorders of the ear. It is now known that disparate drugs that have been found to induce protection from acoustic trauma of the ear have also been found activate Nrf2 in other tissues. The goal of this proposal to test whether Nrf2 activation in the ear is necessary for the protection from acoustic trauma that is provided by one class of protective drugs, antioxidants. Preliminary experiments show that administration of four different antioxidants that are known to activate Nrf2 in other tissues are capable of activating Nrf2 in inner ear cells, with each drug showing activation of a distinctive population of cells. Activation of Nrf2 is assayed by immunostaining for nuclear localized Nrf2. The proposed experiments will ascertain whether activation of Nrf2 in inner ear cells by the chosen drugs is associated with protection of the ear from hearing loss due to noise exposures. This will be tested by the use of mice that are genetically engineered to lack the Nrf2 gene. If the deficient mice fail to show drug induced protection from acoustic trauma that is shown by genetically normal mice, it will mean that Nrf2 activation is essential for the protection afforded by a given drug. Documentation of which cochlear cells show drug- induced Nrf2 activation that is essential for protection from acoustic trauma will broaden the scope of our knowledge concerning the cellular and molecular mechanisms that contribute to vulnerability to and protection from acoustic trauma. Knowledge of which cochlear cells show Nrf2 activation will permit administration of combinations of drugs that activate different cell populations to determine if more efficacious protection from acoustic trauma can thereby be obtained. This will represent a rational approach to optimizing treatments to reduce or prevent acoustic trauma. Extension of the proposed work to include other classes of Nrf2 activating drugs will determine the extent to which Nrf2 can provide a unifying explanation for protection of the ear from insults by disparate drugs. The results may have applications for the treatment and prevention of acoustic trauma, as well as other otologic disorders. PUBLIC HEALTH RELEVANCE: Noise-induced hearing loss is a major public health problem. This project will study tissue defense mechanisms to better understand how the ear can be protected from noise damage and how future treatments can be optimized to better prevent and minimize noise-induced hearing loss.